Upcoming in MS: A Clinical Context Expert Commentary

by John Gever John Gever Deputy Managing Editor, MedPage Today
April 20, 2013

Transcript:

JOHN GEVER: I'm John Gever with MedPage Today, and I'm here with Dr. Jeffrey Cohen of the Cleveland Clinic in Cleveland, and we're here to talk about the landscape of forthcoming therapies for multiple sclerosis. We now have, you could almost call it, a large number of drugs that are effective in preventing relapses and the relapsing forms of the disease. And I'm wondering what is left to tackle. I mean, there are many things left to tackle --

JEFFREY COHEN, MD: Right.

GEVER: Why don't you go ahead and you give me your perspective.

COHEN: Well, first of all, thank you for inviting me to speak today. So, as you pointed out, we've now had treatments for multiple sclerosis since 1993. The initial therapies were all given by self-injection, and for the most part they've served us well. They've proven to be effective, safe, generally well tolerated, but they've had some shortcomings.

So first of all, those medications -- the interferons, glatiramer acetate -- were all administered by injection, which patients dislike. Although they generally have been safe, they've had some side effects, mostly related to the injections; either injection site irritation or flu-like symptoms in the case of the interferons. And also, they all were only modestly effective for patients as a group. So although those medicines represented a major advance in our ability to treat the disease, there certainly was room for improvement, as you said.

So I would say that the next big step in multiple sclerosis was the introduction of fingolimod, the first oral medication approved for multiple sclerosis, which had several advantages. It was given orally, which patients prefer. It's generally been well tolerated, and its major shortcoming has been some rare but potentially serious safety issues: slowing of heart rate with the first dose, the rare occurrence of macular edema, occasional liver abnormalities, and then the potential for infection.

We now have a second oral medication approved, teriflunomide, and several additional oral medications on the horizon: BG-12, possibly laquinimod. And then there also are several medications administered by the intravenous route. So in fact the fifth medication approved for multiple sclerosis was natalizumab, which has the advantage of very potent efficacy, has generally been very well tolerated by patients, but it has the issue of a rare but potentially very serious brain infection, progressive multifocal leukoencephalopathy [PML]. So very shortly we will have one additional intravenous medication, alemtuzumab, which also has the advantage of convenience, potent efficacy, but rare safety issues.

So our expectation is that in the very near future we will have a wide range of MS therapies, ranging from the older injectable therapies with a very proven track record but modest efficacy to convenient oral medications; and medications with much more potent efficacy, but some potential safety issues.

GEVER: So how will clinicians choose among these?

COHEN: That's going to be a very difficult question. I mean, I think we all conceptually feel that we're going to have to come up with a more logical treatment algorithm. But how to match a particular patient with the best medication for them is something that we're going to have to work through.

The hope is that we'll soon learn how to determine whether a patient is not going to benefit from a medication early so that we can make a switch if we have to. And our hope is that, in addition to that, we'll have biomarkers which will allow us to determine whether a patient is responding biologically to a given medication, all with the expectation that we can more logically sequence the treatments in an individual patient, selecting more potent therapies for patients who are at risk for future disability, but maintaining patients on less potent, safer medications when that's appropriate.

I would say that much of our interest now in the MS field is turning to so-called tissue-protective or repair-promoting strategies. As you and I were discussing earlier, our concept of multiple sclerosis is that the early relapsing phase of the disease is driven by the accumulation of abnormal inflammatory lesions within the nervous system, most directly manifested as relapses and lesion activity on MRI. But in many patients with an initial relapsing course, the disease evolves into a so-called progressive phase, where there's less overt inflammatory activity and the more gradual accumulation of disability.

All of our available medications have really only been shown to be effective in the relapsing stage of the disease with their benefit primarily manifested by reduction in the number of relapses or reduction in MRI lesion activity, and then some slowing of disability accumulation and tissue damage on MRI by virtue of reducing inflammation.

But none of those medicines have been shown to be clearly effective in the progressive, we think more degenerative, stage of the disease. So a lot of our attention now is being turned towards strategies that might work in that stage of the disease. So that work includes going back and looking at the previously available therapies to more clearly show, hopefully, that they preserve tissue, to look at whether they have some efficacy in the progressive stage of the disease, but also looking at new treatment strategies.

GEVER: Now, we're at a meeting here.

COHEN: Right.

GEVER: And there was some data just presented yesterday with simvastatin in secondary progressive disease.

COHEN: Right.

GEVER: And I guess that the theory there is that it's an anti-inflammatory drug, and yet secondary progressive is already a very well-advanced form of the disease, where I would have thought that targeting inflammation wouldn't be so effective.

COHEN: Right.

GEVER: That you would be looking for something with a tissue repair type of mechanism. You know, does any of this fit together?

COHEN: Sure. So the statins have received a fair amount of attention over recent years. Some preliminary studies generate conflicting results in relapsing forms of MS. Some studies suggested some benefit on relapses or MRI lesion activity, but some other studies were not as clear cut.

But the statins, in addition to having obviously cholesterol-lowering effects and potential anti-inflammatory effects, also have some biological actions that one would think might preserve tissue or have some repair-promoting properties. So some very interesting work was presented at this conference, suggesting that there may be a benefit in progressive disease. So that requires more follow-up, but the statins would be a very attractive strategy. They're convenient. They're generally well tolerated. They have a very extensive safety record. So that's going to be followed up further.

I would say the other approach that's starting to receive legitimate attention has been cell-based therapies. So hematopoietic stem cell transplantation has been used sort of as the ultra-potent anti-inflammatory strategy, but there also are other types of stem cells that are starting to receive attention, including adult stem cells, which have the advantage that they're more easily obtained than embryonic stem cells and avoid some of the ethical issues. So one particular type of adult stem cells, so-called mesenchymal stem cells, has now been studied in several laboratories.

GEVER: Um-hmm. And I'm wondering, when we get to the point where we have effective tissue protective or tissue regenerative products or therapies, that we would need new assessment tools.

COHEN: Right.

GEVER: Because you wouldn't want to try to re-myelinate a patient who's already had extensive axonal loss.

COHEN: Right.

GEVER: So you need something for reassessing axonal integrity. Do we have those tools at this point?

COHEN: Not at this point, although there are a number of candidate measures. So we've been very lucky in the relapsing stages of the disease that we have a very well-worked-out methodology for screening potential treatments, so MRI studies focusing on gadolinium-enhancing lesions have proven to be very informative in determining which drugs, which treatments should be taken further.

We don't yet have a comparable methodology worked out for either neuroprotective or repair strategies, but the expectation is that it will most likely be some sort of imaging technique. So [things like] diffusion tensor imaging, magnetization transfer imaging, MRI imaging, or so-called optical coherence tomography, high-resolution imaging of the retina -- all have shown promise in being able to measure tissue integrity, and to have some specificity, as you mentioned, for myelin versus axonal damage.

So we're going to need those tools both to guide us on which patients are the best candidates for one of those therapies and also to monitor the effects of the therapy. So, for example, in some of the ongoing studies of cell-based therapies, those imaging techniques are being employed as endpoints.

GEVER: And I think for our final topic, I want to move back a little bit to what we can expect in the short term with the drugs that we're expecting to come on the market soon.

COHEN: Right.

GEVER: Alemtuzumab is a long-acting drug that's still, at least at this point, billed as making a relatively permanent change in the immune response.

COHEN: Right.

GEVER: Obviously that has attractions in some ways, but it also poses some at least theoretical risks, too.

COHEN: Sure, sure.

GEVER: And you know, [with a drug] like natalizumab, you can stop the therapy, and the effect dissipates fairly rapidly. What happens if there's a serious side effect of alemtuzumab?

COHEN: Right. So the long-acting effects of alemtuzumab are a double-edged sword. So they make the drug very convenient to use -- it's administered annually, it's generally well tolerated -- but most of the side effects occur around the time of the infusion, and it has very long-acting benefits. But as you say, some of those same biological effects are its drawbacks.

So the main safety issues that have been seen with alemtuzumab center around antibody-mediated autoimmunity, so thyroid disease and, much more rarely, immune thrombocytopenia, and possibly anti-glomerular basement membrane disease.

What's been seen in the studies to date has been that with a thorough, careful monitoring those complications can be identified early and typically respond to routine therapies. So incorporating monitoring such as that most likely would be part of how we'll utilize that drug.

GEVER: And would we worry at all about PML with alemtuzumab?

COHEN: I think, in principle, any potent immune therapy has the possibility of leading to opportunistic infections, including PML, although, thankfully, PML has not been seen with alemtuzumab at this point.

GEVER: And in fingolimod you mentioned the cardiac effect, and I see that there are a number of other drugs with a similar mechanism that are coming along.

COHEN: Right, right.

GEVER: Is that likely to be a class effect?

COHEN: So the cardiac effects in human are mediated by the type 1 S1P receptor, which is probably involved in its clinical benefit. So I don't think it's going to be possible to dissociate the cardiac effects from the clinical benefits in multiple sclerosis.

Now, what some of the second generation, as it were, selective S1P modulators have as an advantage is that they can be more easily titrated, so we may be able to attenuate the first-dose cardiac effects by gradually starting the medication. They also have the advantage that they're shorter acting drugs, so that if there are any problems that develop with the use, that the drug could be cleared more quickly.

GEVER: And what are the outstanding issues for BG-12, or don't we know yet? Probably we're going to have to wait, really, for post-marketing studies to know the answers, too.

COHEN: Right. So that's one of the things that we're learning in the MS field, as has been learned in other fields, is that as we introduced novel treatments, even with a very large preapproval testing program, that there may be rare or late-appearing safety issues that we've not yet encountered.

So with BG-12, it's looked very clean in the studies to date. Very few significant safety issues have been identified. How well it's tolerated by most patients still needs to be determined. A high proportion develop flushing or gastrointestinal side effects when they first start the medication. How common those are, how severe they are, how long they last, still remains to be seen.

I think the other issue with BG-12 has been that there initially was hope that it would have -- in addition to anti-inflammatory effects -- that it would have the ability to preserve tissue. So far, the data supporting that, that latter hope, have been somewhat conflicting. So for example, the brain atrophy data with BG-12 was less positive than we had expected.

GEVER: Okay. I think that's about all we have time for.

COHEN: Good.

GEVER: But this is extremely informative for me, and I hope for our audience as well, so thank you very much.

COHEN: Well, thank you.

GEVER: Great. I'm John Gever, MedPage Today.

Jeffrey Cohen, MD, PhD, has reported the following financial relationships:

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